Method for producing alkoxymalononitriles

ABSTRACT

A process for preparing 2-cyno-2-alkoxyacetamides of the formula:  
                 
 
     where R 1  is C 1-16 -alkyl or halogen-substituted C 1-16 -alkyl, wherein appropriate alkoxymalonamides of the general formula:  
                 
 
     where R 1  is as defined above, are reacted with a dehydrating agent and the reaction is stopped before the reaction continues to 2-cyano-2-alkoxyacetamides (I).

[0001] The invention relates to a process for preparingalkoxymalononitriles.

[0002] International patent application WO-A-98/31652 describes thepreparation of the anesthetic sevoflurane (fluoromethyl1,1,1,3,3,3-hexafluoro-2-propyl ether) by reacting methoxymalononitrilewith bromine trifluoride. However, WO-A-98/31652 does not disclose thepreparation of methoxymalononitrile.

[0003] It is accordingly an object of the present invention to provide aprocess for preparing alkoxymalononitriles.

[0004] According to the invention, this object is achieved by theprocess according to claim 1.

[0005] It has been found that alkoxymalononitriles of the generalformula

[0006] where R¹ is C₁₋₆-alkyl or halogen-substituted C₁₋₆-alkyl can beprepared by reacting the appropriate alkoxymalonamides of the generalformula

[0007] where R¹ is as defined above with a dehydrating agent.

[0008] “C₁₋₆-alkyl” are here and hereinbelow all linear or branchedalkyl groups having 1-6 carbon atoms, for example methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,tert-pentyl, neopentyl, hexyl or isohexyl.

[0009] “Halogen-substituted C₁₋₆-alkyl” are C₁₋₆-alkyl groups which aremono- or polysubstituted by halogen. Preferred halogens are fluorine,chlorine and bromine. Particular preference is given to fluorine.Examples include: mono-, di- or trifluoromethyl, chloromethyl,bromomethyl, 1- or 2-fluoroethyl, 1- or 2-chloroethyl, 1- or2-bromoethyl and 1-, 2- or 3-fluoropropyl.

[0010] The R¹ radical is preferably methyl or trifluoromethyl.

[0011] Examples of useful dehydrating agents include trifluoroaceticanhydride, dibutyltin oxide, phosphorus oxychloride, phosphorustrichloride and phosphorus pentachloride. Preference is given totrifluoroacetic anhydride and phosphorus oxychloride.

[0012] The dehydrating agent is advantageously used in quantities offrom 0.5 to 6 molar equivalent per amide group of the alkoxymalonamideof the formula II.

[0013] The dehydration is advantageously carried out in a suitablesolvent. Examples of useful solvents include acetonitrile, dioxane,1,2-dichloroethane, toluene, cyclohexane, heptane and octane. Preferenceis given to acetonitrile.

[0014] Preference is given to carrying out the dehydration in boilingsolvent.

[0015] The dehydration is optionally carried out in the presence of aLewis acid. Examples include the following Lewis acids: BF₃, BCl₃, BBr₃,BI₃, SbF₅, AlCl₃, AlBr₃, TiBr₄, TiCl₄, TiCl₃, ZrCl₄, PF₅, FeCl₃ andFeBr₃.

[0016] Preference is given to using AlCl₃ as the Lewis acid.

[0017] The quantity of Lewis acid is preferably from 0.01 to 0.05 molarequivalent.

[0018] The compounds of the formula II can be prepared by knownprocesses. For example, Monatsh. Chem., 1965, 96, 1677-1689 describes aprocess for preparing alkoxymalonamides by reacting methylalkoxyacetates with dialkyl oxalates and reacting the product (dialkylalkoxymalonate) with liquid ammonia.

[0019] The dehydration according to the invention proceeds in twostages, and the intermediate product formed is the corresponding2-cyano-2-alkoxyacetamide of the general formula

[0020] where R¹ is as defined above.

[0021] The 2-cyano-2-alkoxyacetamide (III) may be isolated or thedehydration reaction can be continued until the reaction product of theformula I is obtained.

[0022] To isolate the 2-cyano-2-alkoxyacetamide (III), the progress ofthe dehydration reaction is followed, for example by means of thin layerchromatography. The reaction is stopped at a suitable time, for exampleby cooling the boiling reaction mixture to 50-0° C., preferably to about0° C.

[0023] The workup is effected by known methods, for example by means ofextraction in the presence of a base and subsequent chromatography. Anexample of a useful base is sodium hydrogencarbonate.

[0024] The compounds of the formula III are chiral. They may be eitherin the S-configuration or the R-configuration. The above-describeddehydration results in the racemate which may be separated into the twoisomers by known processes, for example by HPLC chromatography using acolumn having a chiral stationary phase. Chiral stationary phases areknown and commercially available, for example from E. Merck, Waters,Daicel or Macherey & Nagel.

[0025] The compounds of the formula III are novel and likewise form partof the subject-matter of the invention.

[0026] The compounds of the formula III can be converted in a similarmanner to 2-cyanoacetamide, for example using 2-mercaptobenzoic acid toprepare 2-(4-oxobenzothiazin-2-yl)acetamide (N. S. Ibrahim et al.,Heterocycles 1984, 22(8), 1677-1682), using 1,2-diaminobenzene toprepare benzimidazol-2-yl-acetonitrile (T. A. Fairley et al., J. Med.Chem. 1993, 36(12), 1746-1753) or using 2-cyanothioacetamide to preparethiopyridines (R. M. Mohareb et al., Z. Naturforsch. B. Anorg. Chem.Org. Chem. 1986, 41(1), 105-109). Equally, the compounds of the formulaIII are useful for preparing barbiturates, coumarins or vitamins in asimilar manner to the known use of 2-cyanoacetamide.

[0027] The examples hereinbelow illustrate the process according to theinvention.

EXAMPLE 1

[0028] Preparation of Methoxymalononitrile in the Presence of POCl₃

[0029] 13.62 g (87.0 mmol) of POCl₃ and 0.3 g (2.3 mmol) of AlCl₃ wereadded to a solution of 10.0 g (75.7 mmol) of methoxymalonamide in 50 mlof acetonitrile and the reaction mixture was heated to reflux for 4 h.The solvent was distilled off, water was added and the aqueous phaseextracted using diethyl ether (3×50 ml). The organic phase was dried andthe solvent taken off on a rotary evaporator. Purification of theresidue (7.28 g) by means of Kugelrohr distillation (110° C./20 mbar)delivered 4.42 g (61%) of methoxymalononitrile as a colorless liquid.

[0030]¹H NMR (CDCl₃): δ=5.26 (s, 1H); 3.65 (s, 3H).

[0031]¹³C NMR (CDCl₃): δ=110.12 (C≡N); 57.58 (CH₃); 57.33 (CH).

EXAMPLE 2

[0032] Preparation of Methoxymalononitrile in the Presence ofTrifluoroacetic Anhydride

[0033] In a 250 ml round-bottom 3-neck flask, 10 g (75.7 mmol) ofmethoxymalonamide, 22 g (278 mmol) of pyridine and 100 ml of dioxanewere initially charged under argon. At 2-5° C., 48.3 g (230 mmol) oftrifluoroacetic anhydride were added dropwise. The reaction mixture wasallowed to react at room temperature for 24 h. Afterwards, 200 ml ofwater and then 200 ml of methylene chloride were added at 10° C. Afterthe phase separation, extraction was effected once more using 200 ml ofmethylene chloride. The combined organic phases were concentrated, andthe resulting oily crude product (7 g) was distilled (27-30° C./1.6mbar).

[0034] Yield: 2.6 g; 33%

EXAMPLE 3

[0035] 2-Cyano-2-methoxyacetamide

[0036] 6.74 g (44 mmol) of POCl₃ and 152 mg (1.14 mmol) of AlCl₃ wereadded to a solution of 5.0 g (38 mmol) of methoxymalonamide in 100 ml ofacetonitrile at room temperature. This mixture was then heated toboiling under reflux and the progress of the reaction was followed bymeans of TLC (eluent: ethyl acetate/hexane 1/1; R_(f) of the product:0.24). After 2.5 h, the reaction mixture was cooled to 0° C. and pouredcautiously with stirring into a 100 ml of a saturated sodiumhydrogencarbonate solution. This mixture was then extracted 5 times with100 ml of ethyl acetate each time. The combined organic phases weredried over Na₂SO₄ and concentrated by evaporation. Subsequent flashchromatography using Si60 silica gel (column 25×5.5 cm; hexane/ethylacetate 3/1) gave 3.5 g (81%) of 2-cyano-2-methoxyacetamide as acolorless liquid which solidified on cooling.

[0037]¹H NMR (CDCl₃): δ=6.85 (bs, 1H); 6.65 (bs, 1H); 4.65 (s, 1H); 3.63(s, 3H).

[0038]¹³C NMR (CDCl₃): δ=165.2 (C═O); 114.2 (C≡N); 70.6(CH); 58.7 (CH₃).

1. A process for preparing alkoxymalononitriles of the general formula

where R¹ is C₁₋₆-alkyl or halogen-substituted C₁₋₆-alkyl, characterizedin that the appropriate alkoxymalonamides of the general formula

where R¹ is as defined above are reacted with a dehydrating agent.
 2. Aprocess for preparing 2-cyano-2-alkoxyacetamides of the formula

where R¹ is as defined in claim 1, characterized in that the appropriatealkoxymalonamides of the general formula

where R¹ is as defined in claim 1 are reacted with a dehydrating agentand the reaction is stopped before the reaction continues to2-cyano-2-alkoxyacetamides (I).
 3. The process as claimed in claim 2,characterized in that the reaction is stopped by cooling the reactionmixture to 50-0° C.
 4. The process as claimed in any of claims 1 to 3,characterized in that the dehydrating agent used is trifluoroaceticanhydride, dibutyltin oxide, phosphorus oxychloride, phosphorustrichloride or phosphorus pentachloride.
 5. The process as claimed inclaim 4, characterized in that the dehydrating agent is used inquantities of from 0.5 to 6 molar equivalent per amide group of thealkoxymalonamide (II).
 6. The process as claimed in any of claims 1 to5, characterized in that the dehydration is carried out in a boilingsolvent.
 7. The process according to any of claims 1 to 6, characterizedin that the dehydration takes place in the presence of a Lewis acid. 8.The process as claimed in claim 7, characterized in that the Lewis acidused is AlCl₃.
 9. The process as claimed in any of claims 1 to 8,characterized in that R¹ is methyl or trifluoromethyl.
 10. A compound ofgeneral formula

where R¹ is as defined in claim 1.